Drying process for preparing crystalline solid famciclovir

Abstract

The present invention provides a drying process for preparing crystalline solid famciclovir form I comprising the steps of: i) preparing a wet crystalline form of famciclovir; ii) drying the wet crystalline form of famciclovir at a temperature of below 50° C. until the crystalline form contains less than 15% (wt/wt) wetness; and iii) drying the wet crystalline form of famciclovir at a temperature of above 50° C. until the wet crystalline form of famciclovir contains less than 0.05% (wt/wt) water to obtain crystalline solid famciclovir form I.

1. A process for preparing crystalline famciclovir, comprising:
 a) providing a wet crystalline form of famciclovir containing from about 15% to about 40% (wt/wt) solvent; 
 b) drying the wet crystalline form of famciclovir of step a) at a temperature of from about 30° C. to about 50° C. to obtain a wet crystalline form of famciclovir; and 
 c) drying the wet crystalline form obtained from step b) at a temperature higher than 50° C. to obtain a crystalline form of famciclovir containing less than 1% (wt/wt) solvent; 
 wherein the wet crystalline form of famciclovir obtained in step b) contains less than 15% (wt/wt) solvent. 
 
     
     
       2. The process of  claim 1 , wherein the wet crystalline form of famciclovir of step a) contains about 15%-40% (wt/wt) solvent and wherein the wet crystalline form of famciclovir obtained in step b) contains less than 15% (wt/wt) solvent. 
     
     
       3. The process of  claim 1 , wherein the solvent is selected from the group consisting of water, C 1 -C 4  alcohols, C 5 -C 8  alkanes, diisopropyl ether, acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, tert-buthylmethyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutylketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, and propyl acetate and mixtures thereof. 
     
     
       4. The process of  claim 1 , wherein the drying in step b) is performed at a temperature of from about 40° C. to about 50° C. 
     
     
       5. The process of  claim 4 , wherein the drying in step b) is performed at a temperature of about 45° C. 
     
     
       6. The process of  claim 1 , wherein the temperature of step c) ranges from about 50° C. to about 80° C. 
     
     
       7. The process of  claim 1 , wherein the temperature of step c) ranges from about 50° C. to about 65° C. 
     
     
       8. The process of  claim 1 , further comprising drying the crystalline form of famciclovir obtained in step c) at a temperature ranging from about 50° C. to about 80° C. to obtain a crystalline form of famciclovir containing less than 0.5% (wt/wt) solvent. 
     
     
       9. The process of  claim 1 , further comprising drying the crystalline form of famciclovir obtained in step c) at a temperature ranging from about 50° C. to about 80° C. to obtain a crystalline form of famciclovir containing less than 0.05% (wt/wt) solvent. 
     
     
       10. The process of  claim 2 , wherein the solvent is water. 
     
     
       11. The process of one of  claims 1  and  10 , wherein the crystalline form of famciclovir obtained in step c) is famciclovir Form I; wherein Form I is characterized by XRD peaks at 15.5 and 15.9 degree±0.2 degree 2θ. 
     
     
       12. The process of  claim 10 , wherein the crystalline form of famciclovir obtained in step c) is famciclovir Form I containing less than 10% (wt/wt) of another crystalline form of famciclovir; wherein Form I is characterized by XRD peaks at 15.5 and 15.9 degree±0.2 degree θ. 
     
     
       13. The process of  claim 11 , wherein the famciclovir Form I contains less than 10% (wt/wt) of crystalline form II of famciclovir; wherein Form II is characterized by XRD peaks at 16.2 and 16.4 degree±0.2 degree 2θ. 
     
     
       14. The process of  claim 12 , wherein the famciclovir Form I contains less than 2% (wt/wt) of another crystalline form of famciclovir. 
     
     
       15. The process of  claim 14 , wherein the famciclovir Form I contains less than 2% (wt/wt) of crystalline Form II of famciclovir. 
     
     
       16. The process of  claim 1 , further comprising washing the wet crystalline form of famciclovir containing about 40% (wt/wt) or less solvent with a wash solvent prior to step a). 
     
     
       17. The process of  claim 16 , wherein the wash solvent is selected from the group consisting of water, C 1 -C 4  alcohols, C 5 -C 8  alkanes, diisopropyl ether, acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, tert-buthylmethyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutylketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, and propyl acetate and mixtures thereof. 
     
     
       18. The process of  claim 17 , wherein the wash solvent is water. 
     
     
       19. The process of  claim 16 , wherein the wet crystalline form of famciclovir obtained after washing the wet crystalline form of famciclovir containing about 40% (wt/wt) or less solvent prior to step a) contains more than 40% (wt/wt) solvent. 
     
     
       20. The process of one of  claims 1  and  19 , further comprising drying a wet crystalline form of famciclovir containing more than 40% (wt/wt) solvent at a temperature of from about 25° C. to about 35° C. to obtain the wet crystalline form of famciclovir containing 40% (wt/wt) or less solvent of step a). 
     
     
       21. The process of  claim 1 , comprising:
 a) providing a wet crystalline form of famciclovir containing 40% (wt/wt) or less water; 
 b) drying the wet crystalline form of famciclovir of step a) at a temperature of from about 30° C. to about 50° C. to obtain a wet crystalline form of famciclovir containing less than about 15% (wt/wt) water; and 
 c) drying the wet crystalline form obtained in step b) at a temperature higher than 50° C. to obtain a crystalline form I of famciclovir containing less than 1% (wt/wt) water. 
 
     
     
       22. The process of  claim 1 , comprising:
 a) providing a wet crystalline form of famciclovir containing 40% (wt/wt) or less solvent by drying a wet crystalline form of famciclovir containing more than 40% (wt/wt) solvent at a temperature of from about 25° C. to about 35° C. to obtain the wet crystalline form of famciclovir containing 40% (wt/wt) or less solvent; 
 b) drying the wet crystalline form of famciclovir obtained in step a) at a temperature of from about 30° C. to about 50° C. to obtain a wet crystalline form of famciclovir containing less than 15% (wt/wt) solvent; and 
 c) drying the wet crystalline form of famciclovir obtained in step b) at a temperature higher than 50° C. to obtain the crystalline form of famciclovir containing less than 1% (wt/wt) solvent. 
 
     
     
       23. The process of  claim 22 , wherein the solvent is water and the crystalline form of famciclovir obtained in step c) is famciclovir Form I containing less than 1% (wt/wt) water.